1. Field of the Invention
The present invention relates to new pharmacologic usages of inhibitors for a potassium efflux channel to prevent cell death caused by physical and chemical trauma, such as ischemia, hypoxia and contusion. These inhibitors can also protect sickle red blood cells from sickling-unsickling damages.
2. Background Art
It has been established that most cells have both membrane potential-dependent calcium influx channels and potassium efflux channels (FIG. 1). The former channels are opened when the membrane is depolarized to cause calcium entry. This calcium entry can be blocked by calcium channel blockers. The latter channels are opened when the intracellular calcium concentration is increased to cause potassium ion efflux. The potassium efflux channels are different from the calcium entry channels, and were found by Gardos (Biochim. Biophys. Acta 30:653-654, 1958).
In ischemic or traumatic injury of the cells, the membrane is often depolarized as a result of injury. Therefore, the use of calcium channel blocker is known to be beneficial against these insults. However, when the cell membranes are damaged because of these insults, calcium ions may either enter the cells directly through the ruptured holes or released from the intracellular store (see FIG. 1). Since such movements of calcium ions can not be prevented by calcium channel blockers, the use of calcium channel blockers in cell injuries have had a limited success.
The present invention is based upon our study how to protect the cells when the intracellular calcium concentration increases as a result of cell injuries. So far, nobody has studied the importance of the potassium efflux channels. However, the inventor found that inhibitors of a potassium efflux channel have beneficial effects in protecting cells on the occasion of cell injuries. When an increase of cellular calcium ions is caused in organ cells or in red blood cells by ischemia, hypoxia or by physical-chemical damages, the cells lose potassium ions through a potassium efflux channel.
Such a loss causes unbalances both in cellular electrolytes and in water contents, and ultimately kills the cells. Through animal and in vitro experiments, the inventor found that compounds which can inhibit this potassium efflux have beneficial effects in preventing cell death in brain ischemia, spinal cord injury, liver ischemia, and in sickle red blood cells.